This invention pertains to the practice of human medicine, and particularly to the management of diseases of the human heart. It pertains to using the principles of cardiac physiology and electrophysiology for the treatment of clinically demonstrable heart disease.
Each muscle cell, or myocyte, in the ventricles of the human heart is electrically active, maintaining a voltage across the enclosing cell membrane which at rest is negative on the inside surface relative to the outside surface, called the resting potential. Superimposed on this resting voltage can occur a time-limited swing in voltage called an action potential. The transmembrane voltage swings rapidly to a positive value, an event called depolarization. The voltage remains more positive than the resting potential for a period of time, and is said to be in the state of depolarization until it returns all the way to the resting potential. Repolarization is the event or process of returning to the resting potential. The period when the myocyte is depolarized is important in that contraction of the myocyte is occurring as long as the myocyte is depolarized, and because it is depolarized, due to release of calcium ions into the intracellular fluid.
In isolated or unregulated ventricular myocytes, the action potential duration (APD), the time from leaving the resting potential until reachieving the resting potential, ranges from about 200 to 300 milliseconds, averaging about 250 milliseconds. In the intact human heart under normal conditions, the outermost or subepicardial portion of the myocytes display this same APD. But the innermost or subendocardial portion of the myocytes display an APD of about 400 milliseconds during normal function. This local prolonging of APD in the subendocardial layer occurs due to regulation imposed from outside the myocytes by adjacent cells called Purkinje cells which comprise the Bundle Branches and the collected Bundle of His. The Purkinje cells have an APD averaging about 400 milliseconds, whether isolated or in the intact functioning heart. The Purkinje cells regulate the repolarization of the myocytes adjacent to them, delaying the myocyte repolarization until their own repolarization occurs. Since the Purkinje cells are most dense at the subendocardial surface of the ventricular wall, with a decreasing density as one looks outward through the wall, the subendocardial myocytes have a more prolonged APD than the subepicardial myocytes, but only when in an intact heart with fully functioning Purkinje cells and Bundle Branches. The Purkinje cell network has already been known to trigger the coordinated depolarization of myocytes, but its role in regulating repolarization to make a differential in the APD of myocytes according to layer has never before been recognized. This regulation of myocyte repolarization is a part of normal human physiology, and any weakening of it results in a disease state and a weakening of the primary function of the ventricles, which is to pump blood and maintain blood pressure.
The primary mechanism by which Purkinje cells regulate myocytes appears to be depletion of extracellular calcium ions in a restricted extracellular space around the myocytes. This lowered concentration facilitates outward calcium flow and inward sodium flow in the myocytes by the passive sodium-calcium exchange pump. This sustains a net inward current that prolongs the more positive electrical voltage that constitutes the depolarized state. The lowered extracellular calcium may also influence the gated ion channels that complete the repolarization process.
Delaying repolarization and prolonging the depolarized state in the subendocardial portions of the ventricular wall has at least the following beneficial effects at the more macroscopic level.                1) Contraction of the subendocardial layer continues longer than in the subepicardial layer.        2) Tissue pressure remains elevated longer into diastole (the resting phase between heart contractions) in the subendocardium, causing blood to flow into the capillaries in a wave after each contraction, which yields more efficient inflow of blood and oxygen into the subendocardial layer, and less acidosis.        3) The T wave generated by the noninvasive, body surface electrocardiogram (EKG) goes in the same upright direction as the dominant portion of the QRS complex, indicating healthy cardiac function, while without regulation of subendocardial APD the T wave deviates opposite the dominant portion of the QRS into a downward or inverted position.        4) The subendocardial myocytes adapt to optimize regulation by the Purkinje cells, allowing the Purkinje cells to suppress any dysfunctional electrical rhythms that arise from irritable foci in the ventricles or from circulating scroll waves introduced into the ventricles.        5) The Purkinje cells are relatively refractory to electrical stimulation backwards from the myocytes, due to their own optimization as a regulating organ, and thus are protected from serving as a channel for spread of ventricular arrhythmias. This refractoriness also makes the Purkinje cells available to suppress conduction of ventricular arrhythmias under normal pacemaking or artificially imposed overdrive pacing.        6) The contractility of the ventricle as a whole is sustained for a longer period when the Purkinje cells are successfully regulating subendocardial repolarization, yielding increased stroke volume, cardiac output, and energy efficiency.All of these effects yield means of recognizing both healthy and impaired Purkinje function. When Purkinje function is impaired, disease states are caused that justify attempts to restore the normal physiology. These disease states can vary over the surface of a ventricle, for instance if only portions of the ventricles have impaired Purkinje function.        
As used herein, the term “laminar coordination” is defined as the physiologic process by which each laminae, or layers, within the wall of a human heart ventricle undergo synchronized repolarization among themselves, while the sequence of spread of repolarization from one layer of myocardium to another is regulated by an external controller, the Purkinje fiber network of the His bundle and the bundle branches, and is not left to occur according to the intrinsic characteristics of the myocytes. In the normal state in the human, repolarization begins in the subepicardial layer, and then progresses through the more inward layers of myocardium, then last to the subendocardial layer. In the absence of imposition of regulation by the Purkinje cell network, the subendocardial layer would repolarize first, not last. This concept and process of laminar coordination of ventricular repolarization does not appear in any previous literature. The question of the mechanism by which repolarization is locally altered in the deep layers of the ventricles was formulated by Frank Wilson Md. in a 1931 paper, never answered adequately until now, and has not been addressed in the medical and physiology literature since 1957.
Previous mistaken attribution of regulation of ventricular repolarization to thermal gradients or ischemia has resulted in an inability to mitigate clinically the problems which result from defective regulation of ventricular repolarization, including heart failure, subendocardial ischemia, and ventricular arrhythmias.